Mode of Suppression of Pituitary and Gonadal Function After Acute or Prolonged Administration of a Luteinizing Hormone-Releasing Hormone Antagonist in Normal Men*

Publisher Website
Google Scholar
Abstract
LHRH antagonists compete with endogenous LHRH for binding to receptors on pituitary gonadotrophs and thereby inhibit gonadotropin secretion and, consequently, gonadal function. We studied the pituitary and gonadal suppression following single doses and short term administration (1-3 weeks) of a recently developed LHRH antagonist in normal men. First, the antagonist Nal-Glu ([Ac-D2Nal1, D4ClPhe2,D3Pal3,Arg5,DGlu6(AA),DAla10]LHRH), was given as a single sc injection to five normal men at three dose levels of 1, 5, and 20 mg (study I). Serum FSH, immunoreactive LH (IR-LH), bioactive LH (bio-LH), testosterone, and estradiol were measured before and at frequent intervals for 48 h after Nal-Glu administration. Mean serum FSH decreased (P < 0.001) by 28.9 .+-. 5.4% (.+-.SE), 38.2 .+-. 7.9%, and 44.5 .+-. 3.6% after the 1-, 5-, and 20-mg doses, respectively. Mean serum IR-LH decreased (P < 0.001) by 39.0 .+-. 13.8%, 53.2 .+-. 10.0%, and 53.1 .+-. 14.4% after the three doses. Serum bio-LH levels and the ratio of bio-LH/IR-LH decreased (P < 0.001) after the 20-mg dose by 87.8% and 78.5%, respectively. Serum testosterone levels decreased (P < 0.001) more than 78.5% after all Nal-Glu doses. The duration of testosterone suppression, but not the nadir reached, was dose dependent (P = 0.012). Serum estradiol levels also decreased (P < 0.001), but the rate of decrease was slower than that of serum testosterone. The apparent plasma disappearance half-life of Nal-Glu after administration of 5 mg was 12.8 .+-. 2.7 h. The Nal-Glu antagonist also was given daily as a single sc injection of 5 mg to eight normal men for 21 days (study II) or twice daily to five men for 7 days (study III). In study II, serum FSH, IR-LH, bio-LH, testosterone, estradiol, and 17-hydroxyprogesterone were measured daily, immediately before the next injection, and on days 1, 7, and 21 in frequently blood samples drawn for 24 h. The mean serum testosterone level in study II decreased (P < 0.001) from 17.6 .+-. 2.2 to 4.1 .+-. 1.0 nmol/L on day 1, increased (P < 0.05) between days 2 and 8, and then progressively decreased to below 2 nmol/L from day 18 until 24 h after the end of the study. Serum FSH, IR-LH, and bio-LH paralleled those of testosterone. The serum pharmacokinetics of Nal-Glu on days 7 and 21 were almost identical. In study III serum testosterone levels decreased (P < 0.001) and remained suppressed throughout the entire study period. Serum estradiol levels also decreased (P < 0.001), whereas serum 17-hydroxy-progesterone levels did not change. No major side-effects occurred during Nal-Glu administration in any of these studies other than minor local reactions at the injection sites. These results indicate that prolonged administration of the Nal-Glu LHRH antagonist effectively suppresses pituitary and gonadal function. The transient escape from suppression may be prevented by the use of higher or more frequent initial doses.